Building an Investigator-led Clinical Research Network in ......Regional Variation in the Estimated...
Transcript of Building an Investigator-led Clinical Research Network in ......Regional Variation in the Estimated...
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Building an Investigator-led Clinical Research Network in
Hepatocellular Carcinoma an 18-year history
SCRI 2nd Annual Clinical Research Symposium 20161st September 2016 Raffles City
Pierce Chow FRCSE PhDProfessor, Duke-NUS Graduate Medical School
Senior Consultant Surgeon, National Cancer Center, SingaporeSenior Consultant Surgeon, Singapore General Hospital
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Whyan Investigator-lead Asia-Pacific Research Network/Trials Group?
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Singapore is a very small countryin a very big
continent
http://en.wikipedia.org/wiki/List_of_Asian_countries_by_population
*United Nations Population Division estimates for 1 Jul 2012
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If we are so smallWhy should we aspire to be thought- leaders in
Bio-Medicine?
• We need to develop the expertise to achieve better outcomes for our own patients– Copy from the west/other countries OR– Develop expertise in our prevalent diseases
• We want to move up the Bio-Medical value chain– The Sweden of South-east Asia (leader/producer) OR– The powerless downstream consumer of South-east Asia
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Biomedical Research:the only consistent way to achieve
better outcomes in patients
14 days
5 – 8 mm Ø tumours
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Biomedical Discovery Cycle
Basic Scientific
Discoveries
Translational / Animal
Experiment
Phase I Phase II Phase III
Better Clinical
Outcome
Putative
TherapyOr Diagnostic
Clinical Insights
Adapted from KC Soo
Well-conducted prospective clinical studies on areas of pivotal clinical importance is the fastest and most direct
way to bring clinical benefit to patients and influence scientific direction
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Requirements of a good prospective clinical study
• Thought Leadership• Addresses a pivotal clinical issue the decision of which
will impact significantly on clinical practice• Good scientific rationale• Well thought out study design
• Organization• Good track record and excellent logistical ability to carry
out a large trial
• Large Population Catchment• Large number of patients to provide scientifically robust
results – multi-center trials
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addresses an un-met needAn Asia-Pacific
Hepatocellular Carcinoma Trials Group
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Regional Variation in the Estimated Age-Standardized Incidence Rates of Hepatocellular carcinoma.
El-Serag HB. N Engl J Med 2011;365:1118-1127.
1 million new cases a year, 80% in Asia-Pacific sixth most common cancer worldwide, 2nd most
common cause of cancer death (WHO 2015)
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Pierce Chow FRCSE, PhD
Age-Specific HCC Incidences:
USAIn the US, HCC incidences peak at the age of 77.
(El-Serag et al., 2003)
Age-Specific HCC Incidences:
Malaysia
(National Cancer Registry, Malaysia, 2008)
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Men:2nd cause of cancer deaths (previously 3rd) Women: 5th cause of cancer deaths (previously 6th)
GLOBOCAN 2012
HCC: A Global Un-met Clinical NeedMortality approximates incidence
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Pierce Chow FRCSE PhD
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Median overall survival in HCC
0 10 20 30 40 50 60 70 80 90
All
Prostate
Breast
ColorectalKidney
Ovary
StomachLung
Oesophagus
Primary Liver
PancreaticLeukaemias
CML
AML
~ 3-9 month median survival
Percentage of Patients surviving 5 years
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Mortality worse in less develop countriesMen: 5th most Common2nd cause of cancer deaths
Women: 9th most Common6th cause of cancer deaths
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Reasons for poor Clinical Outcomes in Hepatocellular Carcinoma
1. Low research priority. Historically a cancer of poor people in the 3rd world, previously of little interest to industry.
2. Highly heterogeneous cancer, wide geographical, genetic and etiological diversity (chronic Hep B vs Hep C vs NASH)
3. Underlying molecular mechanisms poorly understood- absence of proven therapeutic targets- absence of robust molecular prognostic classifiers
4. Few efficacious therapeutics other than surgery5. Paucity of definitive clinical trials
• More than 1 million new cases a year, 80% in the Asia-Pacific, but few efficacious therapies • 20% of patients are diagnosed at an early stage and benefit from
potentially curative therapies – resection, transplantation, radiofrequency ablation - recurrences common and limit long term survival
• Challenges• Only one useful systemic therapy, sorafenib – no useful adjuvant therapy
• in 1998 – no sorafenib, no RFA, TACE was not proven
• Highly heterogeneous genome• between patients (etiology, geography, ethnicity)
• Significant intra-tumoral heterogeneity
• No validated predictive bio-markers• to match potentially useful therapeutics to the individual patient
Significant Gaps in Hepatocellular Carcinoma
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Hepatocellular Carcinoma:An Unmet Need Globally and in Asia
Surgery is potentially curative in early stage HCC
But 80% are inoperable at time of diagnosis
Paucity of therapeutic targets
Lacks molecular prognostic classifiers
High recurrence rates
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A short historyHow we started the Asia-Pacific
Hepatocellular Carcinoma Trials Group
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The Beginning of the AHCC• Created in 1998 when clinicians from:
• The Chinese University of Hong Kong• The Undayana University, Bali, Indonesia• The University Kebangsaan in Malaysia
• Joined a RCT in HCC proposed by:• the Dept of General Surgery, Singapore General Hospital (SGH ) – no NCCS then• NMRC Clinical Trials and Epidemiology Research Unit (CTERU) - SCRI
• The 1st collaborative oncology trial in the region - became truly Asia-Pacific with centers from : Myanmar, Thailand, Australia,
Korea and New Zealand
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The Asia-Pacific HCC Trials Group
• Aim: to carry out definitive multi-centre trials and other research on HCC in the Asia-Pacific where the disease is endemic
• In 1998 - very few therapeutic options for HCC• relatively few large clinical studies in HCC
• Clinicians looking after HCC patients in the Asia-pacific were bonded by a common need:• for a trials group that seek efficacious treatment for a
common cancer that had few therapeutic options
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Asia-Pacific HCC Trials Group 201640 sites, 17 countries, 1000 patients
Hanoi
Singapore
Seoul, Bundang,
Suwon
Auckland
BangkokDavao City
Penang
Bali
Kuala Lumpur Melbourne
Yangon
Jakarta
Taipei, KaoshiungHong Kong
Manila
Brunei
Ulaan Baator
HCMC
The only multi-national Liver
Cancer Network in the
Asia-Pacific
6 randomized controlled trials since 1998
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Multi-disciplinary KOLS looking after patients with HCC in the Asia-Pacific*
*Outside of China and Japan
Kong et al 2013
AHCC01: NCT00003424. Randomised Trial of Tamoxifen Versus Placebo for the Treatment of Inoperable Hepatocellular Carcinoma.
1997 – 2000NMRC
AHCC02: NCT00041275. Randomized Double Blind Trial Of Megestrol Acetate Versus Placebo For The Treatment Of Inoperable Hepatocellular Carcinoma.
2002 – 2007NCC, SingHealth
AHCC03: NCT00027768. Randomised Trial of Adjuvant Hepatic Intra-Arterial Iodine-131-Lipiodol Following Curative Resection of Hepatocellular Carcinoma
2002 – 2008NMRC
AHCC04: NCT00247260. Phase II dose escalation trial of intra-tumoral Brachysil® in inoperable HCC
2005 – 2006PSiOncology
AHCC05: NCT00712790. Phase I/II Study of SIR-Spheres Plus Sorafenib as First Line Treatment in Patients With Non-Resectable Primary Hepatocellular Carcinoma
2008 – 2009NMRC, Bayer, Sirtex
AHCC06: NCT01135056. Phase III Multi-Centre Open-Label Randomized Controlled Trial of Selective Internal Radiation Therapy (SIRT) Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (SIRveNIB)
2010 – 2016
NMRC, Sirtex
Multi-center Clinical Trials of the AHCC
Clinicaltrials.gov
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Challenges encountered and overcame in building an Investigator-led Clinical
Research Network in Hepatocellular Carcinoma
In the Asia-Pacific
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Asia-Pacific is Highly Heterogenous
• Highly diverse geographical region
• Disparate levels of socio-economic development
• Different ethnic populations
• Main burden of HCC – high incidences of chronic
HBV and HCV
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Inherent Advantages in Conducting HCC Clinical Trials in Asia
• Heterogeneity reflects the clinical reality of the disease– Highly representative, achieve definitive outcomes
• Large number of potential research participants
• Directly benefit patients who otherwise would have no access to new therapies - Economically disadvantaged nations
• Prognostic biomarkers
• Understand various genetic and environmental influences that affect pathology and treatment response – Across different ethnicity and populations
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The Challenges
• Evident gaps in experiences – RCT experience
• Feasibility of conducting good GCP-standard clinical trials
• Rudimentary medical facilities, infrastructure and indemnity assurance
• Differences in the standard of care and cultural practices – affect implementation of study protocol
• Funding and Sponsorship Model
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Meeting the Challenges
• Helping sites to be GCP-compliant– E.g. helping sites to set up IRBs
• Training of clinical trials teams: – Significant investment in time and resources to train,
update and familiarize local staff with study protocol and GCP guideline
• Thorough audits– E.g. 100% audits for AHCC02 trial
• Outsource clinical services to privately run institutions outside of the trial centres– E.g. CT scan imaging to meet inclusion criteria
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Pierce Chow FRCSE PhD
Extensive Site visits, training, audits
Thailand Myanmar
Korea
Phillipines Vietnam
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Continual Dialogue, Frequent one-to-one meetings and Open Channels of
Communications are vital
AHCC06 2nd IM 16/11/12 AHCC03 3rd IM 10/07/14
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Challenges are very different in the different countries –one size does not fit all
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Examples of issues Identified by Members at AHCC06 Investigator’s Meetings
1. Patients at many sites especially in the 3rd World (e.g.Indonesia, Philippines, Myanmar) had problems paying forfollow-up investigations – CT scans, blood tests
2. Results in non-compliance, protocol deviations and patientdrop-outs
3. In other sites e.g. Taiwan, hospital expects the trial to pay forfollow-up investigations once patients enter trial
4. Dis-incentivizes the sites from recruiting patients
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Funding and Paradigm Shift in Clinical ResearchIn the Asia-Pacific
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Paradigm Shift:Conducting Clinical Trials in Asia-Pacific
Over the last 18 years
Due to:•Rapid expansion of pharmaceutical industry•Potential of new markets in the Asia-Pacific•Cost effectiveness
• Relatively cheaper costs of conducting clinical trials
•Improving medical infrastructure•Reduced amount of regulatory barriers compared to the past
Kong, Chow 2013
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Multi-center Clinical Trials of the AHCCAHCC01: NCT00003424. Randomised Trial of Tamoxifen Versus Placebo for the Treatment
of Inoperable Hepatocellular Carcinoma. 1997 – 2000NMRC
AHCC02: NCT00041275. Randomized Double Blind Trial Of Megestrol Acetate Versus Placebo For The Treatment Of Inoperable Hepatocellular Carcinoma.
2002 – 2007NCC, SingHealth
AHCC03: NCT00027768. Randomised Trial of Adjuvant Hepatic Intra-Arterial Iodine-131-Lipiodol Following Curative Resection of Hepatocellular Carcinoma
2002 – 2008NMRC
AHCC04: NCT00247260. Phase II dose escalation trial of intra-tumoral Brachysil® in inoperable HCC
2005 – 2006PSiOncology
AHCC05: NCT00712790. Phase I/II Study of SIR-Spheres Plus Sorafenib as First Line Treatment in Patients With Non-Resectable Primary Hepatocellular Carcinoma
2008 – 2009NMRC, Bayer, Sirtex
AHCC06: NCT01135056. Phase III Multi-Centre Open-Label Randomized Controlled Trial of Selective Internal Radiation Therapy (SIRT) Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (SIRveNIB)
2010 – 2015
NMRC, Sirtex
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Pierce Chow FRCSE PhD
Funding
• Model of co-funding: academic and industrial sources of funding– Maintain the independence of an investigator-initiated trial – Increase the quantum of funding available by tapping on
industry
• AHCC05 (SirSA) - 2008– NMRC $487,000– Therapeutics from Bayer ($1mil) and Sirtex ($1 mil)
• AHCC06 (SirveNIB) - 2010– NMRC $1.67 mil– Sirtex $8.5 mil + $1.9 mil
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Sponsorship Model:Inter-site Agreement
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The Structure of the Asia-Pacific Hepatocellular Carcinoma (AHCC) Trials Group
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Structure of the AHCCA Collaborative Trial Network
• AHCC Trials Group – a collaborative trials group
• Membership by participation in trials • Trials governed by a Steering Committee
• Trials managed by an Academic Research Organization (ARO) – Singapore Clinical Research Institute (SCRI), Network Executives and the Protocol Chair
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Pierce Chow FRCSE PhD
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Investigator-Initiated Trials:The AHCC Trials Group Model
Pierce Chow FRCSE PhD
Protocol ChairSteering Committee
Site
Industry e.g. Sirtex, Bayer,
GSK
Govt Funding Body
e.g. NMRC
Academic CRO SCRICRAs
SiteSite
Site Site
Structure introduces accountability and reduces potential conflict
Regulatory Bodies:IRB, DMC
CRCsCRCs CRCs
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General Meetings5th General Meeting 6th General Meeting
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While trials are initiated by individual PIs they are built from the ground up. Input from sites are crucial important to
ensure buy-in
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Strategic Advantages of a Collaborative Trials Network
• Allows industry to access PIs of different countries from the region
• Facilitates support and broadens collaborations
• Fosters positive relationships among clinician-investigator
• Increases opportunity for scientific breakthrough in future collaborations
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Pierce Chow FRCSE PhD
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Pierce Chow FRCSE PhD
Developing a collaborative platform
• By 2014 the AHCC has reached a stage in its development where it was meaningful to develop a collaborative platform with industrial partners.
• To realize this strategic initiative, a collaborative partnership was developed to facilitate:– clinical projects with industry partners– funding mechanisms that supports the scientific and
administrative infrastructure of the trials group– access to the collective expertise of the group on
scientific and clinical matters pertaining to HCC
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Scientific Forum and General Meeting31st Oct 2014
Pierce Chow FRCSE PhD
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Funded through a collaborative platform with industry to become a regular 6-monthly event
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Where are we today in the AHCC Trials Group?
18 years later
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Asia-Pacific, Phase III, open-label, randomized-controlled study
UPDATE: closure of AHCC06 trial SIRT Yttrium-90 versus Sorafenib in patients with locally
advanced HCC (SIRveNIB)
Closed on 25th May 2016
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Clinical Trajectory and Translational Clinical
Trial
Therapeutics selected on the basis of discoveries in this study
3-monthly follow-up: scans, bloods, cfDNA, CTC
Adjunct Adjuvant Therapy Trial
100 patients5 Asia-Pac centers
RecurrenceBiopsy or resectiontissue samples, cfDNA, CTC
Translational Immunomics
Tumor genomics and heterogeneity
Surgical Resection
Preop scans, bloods, multi-region tissue samples, cfDNA, CTC
PRECISION MEDICINE IN LIVER CANCER ACROSS AN ASIAN PACIFIC NETWORK
Asia-Pacific HCC Trials Group
UPDATE: investigator meeting AHCC07 The Planet Study
NMRC TCR Grant awarded April 2016
Personalized Genomics for drug development
Theme Lead: Zhai Wei WeiIntratumouralHeterogeneity Zhai Wei Wei, Axel Hillmer
Cell-free DNA(Iain Tan)
CTC & single cell omics
(Zhai Wei Wei, Roger Foo)
Immune-modulation and therapyTheme Lead: Salvatore Albani
Immuno-microenvironme
nt(Valerie Chew)
Genomics and epigenomics
of immune subsets in tumour
Immuno-profile of Peripheral T-
cells (Valerie Chew)
Function and mechanisms
SingHealth(Brian Goh)
National Cancer CancerCenter, Bangkok
(Rawisak)
UMMC, KL (Yoong Boon Koon)
Medical City, Manila (Vanessa De Villa)
NUHS(KK Madhavan)
Longitudinal study and Clinical trials
Theme Lead: Pierce Chow1. Adjuvant (P Chow)
2. Recurrence (Toh Han Chong)
Patient derived models
Experimental models, PDX, cell lines – Dan Yock Yong, Tam Wai Leong, Edward Chow, Dan Tenen
Radiomics : Invitrocue, David Townsend
Multi-national Study Sites:
Program Overview
PDX
PDP/Organoids
T T TN
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Investigator Meeting 2016:AHCC07: The PLANET Study
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48 IMS Health Confidential
Study Design
• Study Design : Multi-centre, longitudinal cohort study
• Sample Size : 2000 – 2500 (Retrospective vs Prospective Cases = 30 : 70)
• Patient HCC Diagnosis Period : 1st Jan 2013 - 30th Jun 2018 (Phase 1)
• Start of Registry : 1st Oct 2016
UPDATE: investigator meeting AHCC08 2016The Asia-Pacific Hepatocellular Carcinoma Registry – Phase 1
49 IMS Health Confidential
List of Invited Sites Across Asia – 1st Phase
Australia • Royal Prince Alfred Hospital• University of Adelaide• Austin Hospital
New Zealand• Auckland City Hospital
Japan • Kyorin University School of Medicine• University of Tokyo• Kinki University Hospital• National Cancer Centre
Thailand• National Cancer Institute• Siriraj Hospital, Mahidol
University• Chulabhorn Cancer Centre
Singapore• National Cancer Centre• Singapore General Hospital• National University Hospital
China• Nanjing Bayi Hospital• Zhongshan Hospital, Fudan
University Shanghai• Beijing Cancer Hospital• Sun Yat Sen University Cancer
Centre, Guangzhou• Guangxi Medical University Cancer
Centre• Hunan Province Xiang Ya Hospital• Jiangsu Cancer Centre• Tongji Medical University, Wuhan • Second Affiliated Hospital Zhejiang
University School of Medicine• The Eastern Hepatobiliary Surgery
Hospital, Shanghai• Third Military Medical University
South Korea• Ajou University Hospital• Asan Medical Centre• Korea University Anam Hospital• Seoul National University Bundang
Hospital
Hong Kong Queen Mary Hospital
Taiwan• Chang Gung Memorial Hospital• National Taiwan University Hospital• Taipei Veterans General Hospital• Chang Gung Memorial Hospital – LK• Chang Gung Memorial Hospital – KS• China Medical University Hospital• National Cheng Kung University
Hospital
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Investigator Meeting:AHCC08: Asia-Pacific HCC Registry
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Now includes sites from China and Japan
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AHCC General Meetings
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9th General Meeting 26th August 2016, The Academia, SingHealth
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Asia-Pacific HCC Trials Group 201640 sites, 17 countries, 1000 patients
Hanoi
Singapore
Seoul, Bundang,
Suwon
Auckland
BangkokDavao City
Penang
Bali
Kuala Lumpur Melbourne
Yangon
Jakarta
Taipei, KaoshiungHong Kong
Manila
Brunei
Ulaan Baator
HCMC
The only multi-national Liver
Cancer Network in the
Asia-Pacific
6 randomized controlled trials since 1998
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AHCC Trials Group 2016
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Now includes members from China and Japan
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It is possible to build multi-center
Research Networks
http://en.wikipedia.org/wiki/List_of_Asian_countries_by_population
*United Nations Population Division estimates for 1 Jul 2012
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- Thought Leadership- Organization- Large population
http://en.wikipedia.org/wiki/List_of_Asian_countries_by_population
*United Nations Population Division estimates for 1 Jul 2012
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It is a Virtuous Cycle
Phase III trials are long and tough battles.I would like to thank all our participating PIs who believe in our science and our vision of what is possible and trust that we can do this And to the numerous others who have tried to
made this easier
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…….when the going gets tough……..
The tough gets going!
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Pierce Chow FRCSE PhD
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Thank You!
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Acknowledgement: Rachel Choi BSc (Hons) for assistance with the slides
Pierce Chow FRCS, PhD
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Asia-Pacific Hepatocellular Carcinoma Trials Group 6th General Meeting
31st October 2014
Pierce Chow FRCSE PhD
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AHCC General Meetings
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8th General Meeting 29th Jan 2016, The Academia, SingHealth